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Nature. 2017 Jul 6;547(7661):99-103. doi: 10.1038/nature22393. Epub 2017 May 1.

Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin.

Wang Y1,2, Gao W1,2, Shi X1,2, Ding J2,3, Liu W2, He H2, Wang K2, Shao F2,4.

Author information

1
College of Biological Sciences, China Agricultural University, Beijing 100094, China.
2
National Institute of Biological Sciences, Beijing 102206, China.
3
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
4
National Institute of Biological Sciences, Collaborative Innovation Center for Cancer Medicine, Beijing 102206, China.

Abstract

Pyroptosis is a form of cell death that is critical for immunity. It can be induced by the canonical caspase-1 inflammasomes or by activation of caspase-4, -5 and -11 by cytosolic lipopolysaccharide. The caspases cleave gasdermin D (GSDMD) in its middle linker to release autoinhibition on its gasdermin-N domain, which executes pyroptosis via its pore-forming activity. GSDMD belongs to a gasdermin family that shares the pore-forming domain. The functions and mechanisms of activation of other gasdermins are unknown. Here we show that GSDME, which was originally identified as DFNA5 (deafness, autosomal dominant 5), can switch caspase-3-mediated apoptosis induced by TNF or chemotherapy drugs to pyroptosis. GSDME was specifically cleaved by caspase-3 in its linker, generating a GSDME-N fragment that perforates membranes and thereby induces pyroptosis. After chemotherapy, cleavage of GSDME by caspase-3 induced pyroptosis in certain GSDME-expressing cancer cells. GSDME was silenced in most cancer cells but expressed in many normal tissues. Human primary cells exhibited GSDME-dependent pyroptosis upon activation of caspase-3 by chemotherapy drugs. Gsdme-/- (also known as Dfna5-/-) mice were protected from chemotherapy-induced tissue damage and weight loss. These findings suggest that caspase-3 activation can trigger necrosis by cleaving GSDME and offer new insights into cancer chemotherapy.

PMID:
28459430
DOI:
10.1038/nature22393
[Indexed for MEDLINE]

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